Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study reproduces in experimental animals the sequential development of all the liver lesions seen in the human alcoholic: in 15 baboons fed ethanol, all developed fatty liver, five progressed to hepatitis, and five had cirrhosis. Maintenance of a nutritionally adequate regimen despite the intake of inebriating amounts of ethanol (50% of total calories) was achieved by incorporation of the ethanol in a totally liquid diet. Upon ethanol withdrawal, signs of physical dependence, such as seizures and tremors, developed. Ultrastructural changes of the mitochondria and the endoplasmic reticulum were already present at the fatty liver stage and persisted throughout the hepatitis and cirrhosis. The lesions were similar to those observed in alcoholics (including the inflammation and the central sclerosis) and differed from the alterations produced by choline and protein defiencies. At the fatty liver stage, some "adaptive" increases in activity of microsomal enzymes [aniline hydroxylase (EC 1.14.14.1) and the microsomal ethanol oxidizing system] were observed, but these tended to disappear with the development of hepatitis and cirrhosis. Fat accumulation was also much more pronounced in the animals with the hepatitis as compared with those with simple fatty liver (an 18-fold compared with 3- to 4-fold increase in liver triglycerides). The demonstration that these lesions can develop despite an adequate diet indicates that in addition to correction of the nutritional status, control of alcohol intake is mandatory for the management of patients with alcoholic liver injury.
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PMID:Sequential production of fatty liver, hepatitis, and cirrhosis in sub-human primates fed ethanol with adequate diets. 105 27

Non-arteriosclerotic, virgin and arteriosclerotic, breeder rats were treated with aniline to suppress adrenal steroidogenic capacity and responsiveness to the stress of acute myocardial infarction. After two weeks of aniline treatment, some of the non-arteriosclerotic and arteriosclerotic animals were given two injections of isoproterenol, spaced 24 h apart, to induce massive myocardial infraction. On the 3 rd day, when myocardial necrosis reaches its zenith, the animals were sacrificed. Aniline-induced adrenal insufficiency caused increased mortality, absence of congestive heart failure, cardiac and adrenal enlargement but no evidence of the characteristic intense catabolism and increased corticoid production which attends acute myocardial infarction. Serum enzymes, e.g., SGOT, SGPT and LDH, triglycerides, but not glucose, free fatty acids and cholesterol, became acutely elevated in animals treated with aniline and isoproterenol. Animals developed a fatty liver, beta cell degranulation, post hypophy-sectomy-like changes in their adrenal cortices, unusually severe infarction, marked distention of intermuscular spaces, frequent foci of dystrophic calcification and cartilaginous metaplasia of the papillary muscles. It is believed that aniline-induced adrenal suppression altered the usual pathophysiologic response to acute myocardial infarction.
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PMID:Adrenocortical suppression and myocardial infarction in non-arteriosclerotic (virgin) and arteriosclerotic (breeder) rats. 126 59

The sulphur-containing drug, di-isopropyl-1,3-dithiol-2-ylidenemalonate (Malotilate) protects against the increase in hepatic triglyceride concentration after acute ethanol administration (either 6 g/kg p.o. or 2 g/kg i.p.) in rats. The compound had no influence on the increased hepatic NADH:NAD ratio (measured as the lactate:pyruvate and 3-hydroxybutyrate:acetoacetate ratios) after acute ethanol dosing (2 g/kg i.p.), but was found to lower hepatic acetaldehyde concentrations and prevent some of the disturbances in lipid metabolism observed in liver slices from ethanol-treated animals (e.g. decreased oxidation of [1-14C]palmitate to 14CO2) after this ethanol dose. The drug did not inhibit ethanol metabolism in this acute experiment. Administration of Malotilate to Wistar rats (100 mg/kg/day orally) during chronic feeding of ethanol as 36% of the total calorie intake in a liquid diet, resulted in a lower intake of the alcohol-containing diet by ethanol-fed animals and reduced body weight gain in rats which received the drug, without blood ethanol levels or the ethanol intake (expressed in g/kg body weight/day) being affected. In ethanol-fed animals, Malotilate prevented the production of fatty liver and the adaptive increase in the ethanol elimination rate (EER) normally seen in ethanol-fed animals, although the drug actually caused a slight increase in EER in glucose pair-fed controls. Malotilate did not significantly decrease the degree of induction of microsomal cytochrome P-450 by ethanol, but the increase in aniline hydroxylation was much less marked in animals receiving ethanol and Malotilate, suggesting that the activity of the inducible microsomal ethanol oxidising system (MEOS) may be reduced by the compound. Determination of hepatic acetaldehyde concentrations during ethanol feeding, and during an acute ethanol challenge test following long-term ethanol treatment showed that the compound significantly lowered the level of this ethanol metabolite in the liver under both circumstances. This reduction of hepatic acetaldehyde concentrations, probably resulting in part from the reduced EER as well as increased low-Km aldehyde dehydrogenase activities and glutathione contents seen in the livers of Malotilate-treated rats, are possible mechanisms by which the drug protects against triglyceride accumulation after ethanol administration.
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PMID:The effect of di-isopropyl 1,3 dithiol-2-ylidenemalonate (malotilate) on the hepatic changes induced by ethanol administration in the rat. 314 67

Three experiments were conducted to investigate the effect of diet and estradiol (E2) administration on hepatic microsomal mixed function oxidase (MFO) activity, E2 metabolism, and liver lipid content in male broiler chicks. Broiler chicks (3 weeks of age) were fed either a corn-soybean (CS) diet or a diet containing fish meal, alfalfa meal, and torula yeast (FAY) for 19 days in Experiments 1 and 3 and for 14 days in Experiment 2, respectively. Half of the chicks were implanted with tubes containing E2. In all experiments when the chicks were estrogenized, feeding FAY significantly lowered liver lipid content and plasma E2 concentration. Activity of hepatic microsomal aniline hydroxylase and content of cytochrome P-450 were significantly increased by feeding FAY with or without E2 administration. The chicks fed the CS diet had a significantly lower content of cytochrome P-450 when E2 was administered. Activities of aminopyrine demethylase and nicotinamide adenine dinucleotide phosphate, reduced (NADPH)-cytochrome C reductase did not differ significantly between the diets. In in vitro studies, conversion of 14C-E2 into the water soluble fraction was significantly increased in microsomes from chicks fed the FAY diet as compared to ones from chicks fed the CS diet. The results suggest that some of the hepatic microsomal functions on the CS diet are modified by the change in diet composition and that these modifications are probably associated with E2 metabolism and occurrence of fatty liver.
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PMID:Effect of dietary composition and estradiol implants on hepatic microsomal mixed function oxidase and lipid deposition in growing chicks. 651 66

Monkeys (Macaca nemestrina) were divided into four groups, and each group was fed a particular diet. The variables in the diets were as follows: diet A, 0.3 mg cholesterol/kcal nutrient; diet B, 1.0 mg cholesterol/kcal nutrient; diet C, 0.3 mg cholesterol/kcal nutrient, ethanol (36% of calories); diet D, 1.0 mg cholesterol/kcal nutrient, ethanol (36% of calories). Monkeys on the diets containing ethanol developed fatty liver. Mitochondria from ethanol-fed animals demonstrated significant decreases in uncoupler-stimulated, state 3, and state 4 succinate oxidation activity; respiratory control ratio; and ATP content. Liver microsomes isolated from the ethanol-fed groups demonstrated increased ethanol oxidizing activity with either NADPH or H2O2 as cosubstrate. Aniline hydroxylase and aminopyrine-N-demethylase activities were also elevated in ethanol-fed animals. The alterations in these functional properties were related primarily to ethanol in the diets. Cholesterol, while being less of a perturbant than ethanol, did elicit a significant decrease in cytochrome oxidase activity of mitochondria and a small but statistically significant increase in microsomal-associated ethanol oxidation activity. It appeared to potentiate the effect of ethanol in lowering mitochondrial respiratory control and ATP concentrations.
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PMID:Effect of dietary ethanol and cholesterol on metabolic functions of hepatic mitochondria and microsomes from the monkey, Macaca nemestrina. 702 93

The subchronic toxicity of 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153) was investigated in rats after 13 weeks of dietary exposure. Groups of 10 male and 10 female rats were administered PCB 153 in their diet at levels of 0.05, 0.50, 5.0 or 50 ppm for 13 weeks. The control groups received the diet containing 4% corn oil. Growth rate and dietary consumption were not affected by treatment. Clinical signs of toxicity were not observed. Enlarged, fatty liver was observed in treated animals at necropsy, but most were confined to the two highest dose groups. Increased hepatic microsomal ethoxyresorufin-O-deethylase, aminopyrine-N-demethylase and aniline hydroxylase activities occurred in high-dose groups of both sexes, with increased ethoxyresorufin-O-deethylase activity being observed starting at 0.05 ppm in females and at 0.5 ppm in males. Treatment-related reduction in hepatic and pulmonary vitamin A was seen in the highest dose group of both sexes. Changes in brain biogenic amines and intermediate products were observed mainly in females; these included decreased dopamine and 5-hydroxytryptamine concentrations in the frontal cortex region, and dihydroxyphenylacetic acid in the caudate nucleus region at 5.0 and 50 ppm. Female rats appeared to be more sensitive to the neurotoxic effects of PCB 153 than males. Dose-dependent histological changes were observed in the thyroid and liver of rats of both sexes and significant changes occurred at 5.0 and 50 ppm. Based on these data, the no-observable-adverse-effect level (NOAEL) of PCB 153 was judged to be 0.5 ppm in the diet or 34 micrograms kg-1 body wt. day-1.
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PMID:Toxicity of 2,2',4,4',5,5'-hexachlorobiphenyl in rats: effects following 90-day oral exposure. 893 85

Juvenile visceral steatosis (jvs) mice, isolated from the C3H-H-2 degrees strain, exibit a systemic carnitine deficiency (SCD) phenotype and develop fatty liver, hyperammonemia and hypoglycemia. This phenotype is caused by a missense mutation (Leu352Arg) of a sodium-dependent carnitine/organic cation transporter, Octn2 (Slc22a5). The jvs mouse could be a useful model for pharmacokinetics and drug metabolism studies concerning Octn2 substrate drugs. In the present study, the effects of the SCD phenotype on the cytochrome P450 (P450 or CYP) dependent activities of four endobiotic and seven xenobiotic oxidations catalyzed by liver and kidney microsomes from jvs mice were investigated. The jvs-type mutation was genotyped by PCR-RFLP. The contents of total P450 and NADPH-P450 reductase were similar in the the liver microsomes from male or female mice of the wild-type and those heterozygous or homozygous for the jvs-type mutation. The 6beta-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) based on the protein contents were 1.2- to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared to jvs/wt- or wt/wt-type mice. Coumarin 7-hydroxylation activities (marker for Cyp2a) were decreased to 0.7-fold in the male jvs/jvs-type mice. The activities of lauric acid 12-hydroxylation (a marker for Cyp4a) and aniline p-hydroxylation (a marker for Cyp2e1) in liver microsomes were increased 1.4- to 1.9-fold in female jvs/jvs-type mice. Genotoxic activation of 2-aminofluorene (a marker for Cyp4b1) by male and female mouse kidney microsomes were not affected by the SCD phenotype. These results demonstrated that the SCD phenotype affected the P450-dependent catalytic activities in liver microsomes. The jvs mouse could provide valuable information in drug interaction and drug metabolism studies of OCTN2 substrate drugs and new compounds in development.
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PMID:Activities of cytochrome p450 enzymes in liver and kidney microsomes from systemic carnitine deficiency mice with a gene mutation of carnitine/organic cation transporter. 1561 52